Agents, such as morphine, DAGO and sufentanil, DADL and DPDPE, or dexmedetomidine, clonidine and ST-91 administered intrathecally in species ranging from mouse through primate have been shown to produce a powerful analgesia in the absence of prominent effects upon motor or nociceptive sensory processing. By the use of classical pharmacological procedures, including agonist dose response curves, and the relative potency of various competitive antagonists, it has been show that these agents are exerting their actions through spinal mu,mu and alpha2 receptors, respectively. Consistent with the properties of these three classes of receptors, it has been shown that chronic administration leads to a reduction in effect which is not due to changes in drug kinetics or metabolism, i.e., it is a receptor selective, temporally reversible tolerance i.e., minimal if any detectable cross tolerance between agonists of the three receptors. In our work, it was, however, found that the magnitude of shift in the test dose response curves for different agonists (i.e., morphine and sufentanil) acting at the same receptor was different in spite of the fact that the different drugs were continuously administered in several concentrations which were equieffective. Given that drug effects were proportional to occupancy, it was speculated that the differential shift might reflect different degrees of receptor inactivation induced by these agent because of differences in the occupancy required to produce the desired effect during chronic exposure. Preliminary results supported that speculation and leads to the following four hypotheses based on receptor theory which are the focus of this proposal: 1) Inactivation of populations of spinal receptors by the intrathecal pretreatment with different irreversible antagonists (mu:beta-funatrexamine;mu/delta/kappa beta- chlornaltrexamine;delta: DALCE;mu1:naloxoneazine;alpha adrenergic:EEDQ) will produce different degrees of rightward shift in the intrathecal dose response curves for agents which exert their effects though the respective inactivated receptors, i.e., they will differ in the magnitude of the population required to produce a given effect (a measure of receptor reserve and intrinsic efficacy); 2)Different spinal agonist, which exert their effect though the same receptor but differ in their intrinsic activity, will show differential sifts in the same receptor but differ in their intrinsic activity, will show differential shifts in their dose responses curse (high efficacy yields smaller dose shifts for a given effect); 3) agents which act at the same receptor but differ in intrinsic efficacy will show asymmetric cross tolerance; and 4) Increasing the magnitude of a given noxous stimulus (thermal), requiring an increase agonist occupancy will produce a rightward shift in the intrathecal agonist does response curve such that agents with high intrinsic efficacy will show less shift than agents with low intrinsic efficacy. The significance of efficacy in nociceptive therapy has only been tentatively addressed. The preliminary studies, however, strongly suggest that it my play a very prominent role in determining drug utility in acute and severe pain, as well as in the characteristics of actions of receptor selective agents employed for long term therapy as in chronic pain.